Taxanes having a c10 Heterosubstituted acetate substituent

ABSTRACT

Taxanes having a heterosubstituted acetate substituent at C(10), a hydroxy substituent at C(7), and a range of C(2), C(9), C(14), and side chain substituents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 09/775,912filed Feb. 2, 2001, now U.S. Pat. No. 6,664,275 which claimed priorityfrom U.S. provisional application Ser. No. 60/179,669, filed on Feb. 2,2000.

BACKGROUND OF THE INVENTION

The present invention is directed to novel taxanes which haveexceptional utility as antitumor agents.

The taxane family of terpenes, of which baccatin III and taxol aremembers, has been the subject of considerable interest in both thebiological and chemical arts. Taxol itself is employed as a cancerchemotherapeutic agent and possesses a broad range of tumor-inhibitingactivity. Taxol has a 2′R, 3′S configuration and the followingstructural formula:

wherein Ac is acetyl.

Colin et al. reported in U.S. Pat. No. 4,814,470 that certain taxolanalogs have an activity significantly greater than that of taxol. Oneof these analogs, commonly referred to as docetaxel, has the followingstructural formula:

Although taxol and docetaxel are useful chemotherapeutic agents, thereare limitations on their effectiveness, including limited efficacyagainst certain types of cancers and toxicity to subjects whenadministered at various doses. Accordingly, a need remains foradditional chemotherapeutic agents with improved efficacy and lesstoxicity.

SUMMARY OF THE INVENTION

Among the objects of the present invention, therefore, is the provisionof taxanes which compare favorably to taxol and docetaxel with respectto efficacy as anti-tumor agents and with respect to toxicity. Ingeneral, these taxanes possess a heterosubstituted acetate substituentat C-10, a hydroxy substituent at C-7 and a range of C-3′ substituents.

Briefly, therefore, the present invention is directed to the taxanecomposition, per se, to pharmaceutical compositions comprising thetaxane and a pharmaceutically acceptable carrier, and to methods ofadministration.

Other objects and features of this invention will be in part apparentand in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In one embodiment of the present invention, the taxanes of the presentinvention correspond to structure (1):

wherein

-   -   R₂ is acyloxy;    -   R₇ is hydroxy;    -   R₉ is keto, hydroxy, or acyloxy;    -   R₁₀ is heterosubstituted acetate;    -   R₁₄ is hydrido or hydroxy;    -   X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl,        phenyl or heterocyclo;    -   X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀;    -   X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;    -   Ac is acetyl; and    -   R₇, R₉, and R₁₀ independently have the alpha or beta        stereochemical configuration.

In one embodiment, R₂ is an ester (R_(2a)C(O)O—), a carbamate(R_(2a)R_(2b)NC(O)O—), a carbonate (R_(2a)OC(O)O—), or a thiocarbamate(R_(2a)SC(O)O—) wherein R_(2a) and R_(2b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferredembodiment, R₂ is an ester (R_(2a)C(O)O—), wherein R_(2a) is aryl orheteroaromatic. In another preferred embodiment, R₂ is an ester(R_(2a)C(O)O—), wherein R_(2a) is substituted or unsubstituted phenyl,furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R₂is benzoyloxy.

While R₉ is keto in one embodiment of the present invention, in otherembodiments R₉ may have the alpha or beta stereochemical configuration,preferably the beta stereochemical configuration, and may be, forexample, α- or β-hydroxy or α- or β-acyloxy. For example, when R₉ isacyloxy, it may be an ester (R_(9a)C(O)O—), a carbamate(R_(9a)R_(9b)NC(O)O—), a carbonate (R_(9a)OC(O)O—), or a thiocarbamate(R_(9a)SC(O)O—) wherein R_(9a) and R_(9b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R₉ is an ester(R_(9a)C(O)O—), R_(9a) is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstituted arylor substituted or unsubstituted heteroaromatic. Still more preferably,R₉ is an ester (R_(9a)C(O)O—), wherein R_(9a) is substituted orunsubstituted phenyl, substituted or unsubstituted furyl, substituted orunsubstituted thienyl, or substituted or unsubstituted pyridyl. In oneembodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) is methyl, ethyl, propyl(straight, branched or cyclic), butyl (straight, branched or cyclic),pentyl, (straight, branched or cyclic), or hexyl (straight, branched orcyclic). In another embodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) issubstituted methyl, substituted ethyl, substituted propyl (straight,branched or cyclic), substituted butyl (straight, branched or cyclic),substituted pentyl, (straight, branched or cyclic), or substituted hexyl(straight, branched or cyclic) wherein the substituent(s) is/areselected from the group consisting of heterocyclo, alkoxy, alkenoxy,alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro,amino, amido, thiol, ketal, acetal, ester and ether moieties, but notphosphorous containing moieties.

In one embodiment, R₁₀ is R_(10a)C(O)O— wherein R_(10a) isheterosubstituted methyl, said heterosubstituted methyl moiety lacking acarbon atom which is in the beta position relative to the carbon atom ofwhich R_(10a) is a substituent. The heterosubstituted methyl iscovalently bonded to at least one heteroatom and optionally withhydrogen, the heteroatom being, for example, a nitrogen, oxygen,silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatommay, in turn, be substituted with other atoms to form a heterocyclo,alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy,acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ethermoiety. Exemplary R₁₀ substituents include R_(10a)COO— wherein R_(10a)is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl,acetoxymethyl, acyloxymethyl, or methylthiomethyl.

Exemplary X₃ substituents include substituted or unsubstituted C₂ to C₈alkyl, substituted or unsubstituted C₂ to C₈ alkenyl, substituted orunsubstituted C₂ to C₈ alkynyl, substituted or unsubstitutedheteroaromatics containing 5 or 6 ring atoms, and substituted orunsubstituted phenyl. Exemplary preferred X₃ substituents includesubstituted or unsubstituted ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.

Exemplary X₅ substituents include —COX₁₀, —COOX₁₀ or —CONHX₁₀ whereinX₁₀ is substituted or unsubstituted alkyl, alkenyl, phenyl orheteroaromatic. Exemplary preferred X₅ substituents include —COX₁₀,—COOX₁₀ or —CONHX₁₀ wherein X₁₀ is (i) substituted or unsubstituted C₁to C₈ alkyl such as substituted or unsubstituted methyl, ethyl, propyl(straight, branched or cyclic), butyl (straight, branched or cyclic),pentyl (straight, branched or cyclic), or hexyl (straight, branched orcyclic); (ii) substituted or unsubstituted C₂ to C₈ alkenyl such assubstituted or unsubstituted ethenyl, propenyl (straight, branched orcyclic), butenyl (straight, branched or cyclic), pentenyl (straight,branched or cyclic) or hexenyl (straight, branched or cyclic); (iii)substituted or unsubstituted C₂ to C₈ alkynyl such as substituted orunsubstituted ethynyl, propynyl (straight or branched), butynyl(straight or branched), pentynyl (straight or branched), or hexynyl(straight or branched); (iv) substituted or unsubstituted phenyl, or (v)substituted or unsubstituted heteroaromatic such as furyl, thienyl, orpyridyl, wherein the substituent(s) is/are selected from the groupconsisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy,protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal,acetal, ester and ether moieties, but not phosphorous containingmoieties.

In one embodiment of the present invention, the taxane corresponds tostructure 1, X₅ is —COX₁₀ wherein X₁₀ is phenyl or —COOX₁₀ wherein X₁₀is t-butoxycarbonyl, and R₁₀ is R_(10a)C(O)O— wherein R_(10a) isalkoxymethyl, preferably methoxymethyl or ethoxymethyl. In anotherembodiment of the present invention the taxane corresponds to structure1, X₅ is —COX₁₀ wherein X₁₀ is phenyl or —COOX₁₀ wherein X₁₀ ist-butoxycarbonyl, and R₁₀ is R_(10a)C(O)O— wherein R_(10a) isacyloxymethyl, preferably acetoxymethyl.

In another embodiment of the present invention, the taxane correspondsto structure 1, X₅ is −COX₁₀ wherein X₁₀ is phenyl or —COOX₁₀ whereinX₁₀ is t-butoxycarbonyl, R₁₀ is R_(10a)C(O)O— wherein R_(10a) isalkoxymethyl such as methoxymethyl or ethoxymethyl, or aryloxymethylsuch as phenoxymethyl, and X₃ is heterocyclo. In another embodiment ofthe present invention the taxane corresponds to structure 1, X₅ is—COX₁₀ wherein X₁₀ is phenyl or —COOX₁₀ wherein X₁₀ is t-butoxycarbonyl,and R₁₀ is R_(10a)C(O)O— wherein R_(10a) is acyloxymethyl, preferablyacetoxymethyl, and X₃ is heterocyclo.

In one preferred embodiment of the present invention, the taxanes of thepresent invention correspond to structure (2):

wherein

-   -   R₇ is hydroxy;    -   R₁₀ is heterosubstituted acetate;    -   X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, or        heterocyclo, wherein alkyl comprises at least two carbon atoms;    -   X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; and    -   X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.        For example, in this preferred embodiment in which the taxane        corresponds to structure (2), R₁₀ is R_(10a)COO— wherein R_(10a)        is heterosubstituted methyl, more preferably heterosubstituted        methyl wherein the heterosubsituents are selected from the group        consisting of nitrogen, oxygen, silicon, phosphorous, boron,        sulfur, or halogen atoms, still more preferably        heterosubstituted methyl wherein the heterosubstituent is alkoxy        or acyloxy. While R_(10a) is selected from among these, in one        embodiment X₃ is selected from substituted or unsubstituted        alkyl, alkenyl, phenyl or heterocyclo, more preferably        substituted or unsubstituted alkenyl, phenyl or heterocyclo,        still more preferably substituted or unsubstituted phenyl or        heterocyclo, and still more preferably heterocyclo such as        furyl, thienyl or pyridyl. While R_(10a) and X₃ are selected        from among these, in one embodiment X₅ is selected from —COX₁₀        wherein X₁₀ is phenyl, alkyl or heterocyclo, more preferably        phenyl. Alternatively, while R_(10a) and X₃ are selected from        among these, in one embodiment X₅ is selected from —COX₁₀        wherein X₁₀ is phenyl, alkyl or heterocyclo, more preferably        phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is alkyl, preferably        t-butyl. Among the more preferred embodiments, therefore, are        taxanes corresponding to structure 2 in which (i) X₅ is —COOX₁₀        wherein X₁₀ is tert-butyl or X₅ is —COX₁₀ wherein X₁₀ is        phenyl, (ii) X₃ is substituted or unsubstituted cycloalkyl,        alkenyl, phenyl or heterocyclo, more preferably substituted or        unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl,        still more preferably unsubstituted isobutenyl, furyl, thienyl        or pyridyl, and (iii) R₁₀ is alkoxyacetyl aryloxyacetyl, or        acyloxyacetyl.

Taxanes having the general formula 1 may be obtained by treatment of ab-lactam with an alkoxide having the taxane tetracyclic nucleus and aC-13 metallic oxide substituent to form compounds having a b-amido estersubstituent at C-13 (as described more fully in Holton U.S. Pat. No.5,466,834), followed by removal of the hydroxy protecting groups. Theβ-lactam has the following structural formula (3):

wherein P₂ is a hydroxy protecting group and X₃ and X₅ are as previouslydefined and the alkoxide has the structural formula (4):

wherein M is a metal or ammonium, P₇ is a hydroxy protecting group andR₁₀ is as previously defined. The alkoxide may be prepared from10-deacetylbaccatin III by selective esterification of the C-10 hydroxylgroup and then protection of the C-7 hydroxyl group (as described morefully in Holton et al., PCT Patent Application WO 99/09021) followed bytreatment with a metallic amide.

Alternatively, taxanes having the general formula 1 may be obtained bytreatment of a b-lactam with an alkoxide having the taxane tetracyclicnucleus and a C-13 metallic oxide substituent to form compounds having ab-amido ester substituent at C-13 (as described more fully in HoltonU.S. Pat. No. 5,466,834), followed by selective deprotection of theC(10) hydroxy group and reaction with an acylating agent such as analkoxyacetyl halide.

Derivatives of 10-deacetylbaccatin III having alternative substituentsat C(2), C(9) and C(14) and processes for their preparation are known inthe art. Taxane derivatives having acyloxy substituents other thanbenzoyloxy at C(2) may be prepared, for example, as described in Holtonet al., U.S. Pat. No. 5,728,725 or Kingston et al., U.S. Pat. No.6,002,023. Taxanes having acyloxy or hydroxy substituents at C(9) inplace of keto may be prepared, for example as described in Holton etal., U.S. Pat. No. 6,011,056 or Gunawardana et al., U.S. Pat. No.5,352,806. Taxanes having a beta hydroxy substituent at C(14) may beprepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.

Processes for the preparation and resolution of the β-lactam startingmaterial are generally well known. For example, the β-lactam may beprepared as described in Holton, U.S. Pat. No. 5,430,160 and theresulting enatiomeric mixtures of β-lactams may be resolved by astereoselective hydrolysis using a lipase or enzyme as described, forexample, in Patel, U.S. Pat. No. 5,879,929 Patel U.S. Pat. No. 5,567,614or a liver homogenate as described, for example, in PCT PatentApplication No. 00/41204. In a preferred embodiment in which theβ-lactam is furyl substituted at the C(4) position, the β-lactam can beprepared as illustrated in the following reaction scheme:

wherein Ac is acetyl, NEt₃ is triethylamine, CAN is ceric ammoniumnitrate, and p-TsOH is p-toluenesulfonic acid. The beef liver resolutionmay be carried out, for example, by combining the enatiomeric β-lactammixture with a beef liver suspension (prepared, for example, by adding20 g of frozen beef liver to a blender and then adding a pH 8 buffer tomake a total volume of 1 L).

Compounds of formula 1 of the instant invention are useful forinhibiting tumor growth in mammals including humans and are preferablyadministered in the form of a pharmaceutical composition comprising aneffective antitumor amount of a compound of the instant invention incombination with at least one pharmaceutically or pharmacologicallyacceptable carrier. The carrier, also known in the art as an excipient,vehicle, auxiliary, adjuvant, or diluent, is any substance which ispharmaceutically inert, confers a suitable consistency or form to thecomposition, and does not diminish the therapeutic efficacy of theantitumor compounds. The carrier is “pharmaceutically orpharmacologically acceptable” if it does not produce an adverse,allergic or other untoward reaction when administered to a mammal orhuman, as appropriate.

The pharmaceutical compositions containing the antitumor compounds ofthe present invention may be formulated in any conventional manner.Proper formulation is dependent upon the route of administration chosen.The compositions of the invention can be formulated for any route ofadministration so long as the target tissue is available via that route.Suitable routes of administration include, but are not limited to, oral,parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal,subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal), topical (nasal, transdermal,intraocular), intravesical, intrathecal, enteral, pulmonary,intralymphatic, intracavital, vaginal, transurethral, intradermal,aural, intramammary, buccal, orthotopic, intratracheal, intralesional,percutaneous, endoscopical, transmucosal, sublingual and intestinaladministration.

Pharmaceutically acceptable carriers for use in the compositions of thepresent invention are well known to those of ordinary skill in the artand are selected based upon a number of factors: the particularantitumor compound used, and its concentration, stability and intendedbioavailability; the disease, disorder or condition being treated withthe composition; the subject, its age, size and general condition; andthe route of administration. Suitable carriers are readily determined byone of ordinary skill in the art (see, for example, J. G. Nairn, in:Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack PublishingCo., Easton, Pa., (1985), pp. 1492-1517, the contents of which areincorporated herein by reference).

The compositions are preferably formulated as tablets, dispersiblepowders, pills, capsules, gelcaps, caplets, gels, liposomes, granules,solutions, suspensions, emulsions, syrups, elixirs, troches, dragees,lozenges, or any other dosage form which can be administered orally.Techniques and compositions for making oral dosage forms useful in thepresent invention are described in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

The compositions of the invention for oral administration comprise aneffective antitumor amount of a compound of the invention in apharmaceutically acceptable carrier. Suitable carriers for solid dosageforms include sugars, starches, and other conventional substancesincluding lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar,mannitol, sorbitol, calcium phosphate, calcium carbonate, sodiumcarbonate, kaolin, alginic acid, acacia, corn starch, potato starch,sodium saccharin, magnesium carbonate, tragacanth, microcrystallinecellulose, colloidal silicon dioxide, croscarmellose sodium, talc,magnesium stearate, and stearic acid. Further, such solid dosage formsmay be uncoated or may be coated by known techniques; e.g., to delaydisintegration and absorption.

The antitumor compounds of the present invention are also preferablyformulated for parenteral administration, e.g., formulated for injectionvia intravenous, intraarterial, subcutaneous, rectal, subcutaneous,intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal routes. The compositions of theinvention for parenteral administration comprise an effective antitumoramount of the antitumor compound in a pharmaceutically acceptablecarrier. Dosage forms suitable for parenteral administration includesolutions, suspensions, dispersions, emulsions or any other dosage formwhich can be administered parenterally. Techniques and compositions formaking parenteral dosage forms are known in the art.

Suitable carriers used in formulating liquid dosage forms for oral orparenteral administration include nonaqueous,pharmaceutically-acceptable polar solvents such as oils, alcohols,amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, aswell as water, saline solutions, dextrose solutions (e.g., DW5),electrolyte solutions, or any other aqueous, pharmaceutically acceptableliquid.

Suitable nonaqueous, pharmaceutically-acceptable polar solvents include,but are not limited to, alcohols (e.g., α-glycerol formal, β-glycerolformal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol,t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin(glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, laurylalcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fattyalcohols such as polyalkylene glycols (e.g., polypropylene glycol,polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g.,dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide,N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamideamides,2-pyrrolidinone, 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone);esters (e.g., 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esterssuch as monoacetin, diacetin, and triacetin, aliphatic or aromaticesters such as ethyl caprylate or octanoate, alkyl oleate, benzylbenzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerinsuch as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate,ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acidesters of sorbitan, fatty acid derived PEG esters, glycerylmonostearate, glyceride esters such as mono, di, or tri-glycerides,fatty acid esters such as isopropyl myristrate, fatty acid derived PEGesters such as PEG-hydroxyoleate and PEG-hydroxystearate, N-methylpyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyesterssuch as poly(ethoxylated)₃₀₋₆₀ sorbitol poly(oleate)₂₋₄,poly(oxyethylene)₁₅₋₂₀ monooleate, poly(oxyethylene)₁₅₋₂₀ mono12-hydroxystearate, and poly(oxyethylene)₁₅₋₂₀ mono ricinoleate,polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitanmonooleate, polyoxyethylene-sorbitan monopalmitate,polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitanmonostearate, and Polysorbate® 20, 40, 60 or 80 from ICI Americas,Wilmington, Del., polyvinylpyrrolidone, alkyleneoxy modified fatty acidesters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylatedcastor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution),saccharide fatty acid esters (i.e., the condensation product of amonosaccharide (e.g., pentoses such as ribose, ribulose, arabinose,xylose, lyxose and xylulose, hexoses such as glucose, fructose,galactose, mannose and sorbose, trioses, tetroses, heptoses, andoctoses), disaccharide (e.g., sucrose, maltose, lactose and trehalose)or oligosaccharide or mixture thereof with a C₄-C₂₂ fatty acid(s)(e.g.,saturated fatty acids such as caprylic acid, capric acid, lauric acid,myristic acid, palmitic acid and stearic acid, and unsaturated fattyacids such as palmitoleic acid, oleic acid, elaidic acid, erucic acidand linoleic acid)), or steroidal esters); alkyl, aryl, or cyclic ethershaving 2-30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, dimethylisosorbide, diethylene glycol monoethyl ether); glycofurol(tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having3-30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutylketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolanes,hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon,tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), ortetramethylenesulfoxide); oils of mineral, vegetable, animal, essentialor synthetic origin (e.g., mineral oils such as aliphatic or wax-basedhydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic basedhydrocarbons, and refined paraffin oil, vegetable oils such as linseed,tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed,coconut, palm, olive, corn, corn germ, sesame, persic and peanut oil andglycerides such as mono-, di- or triglycerides, animal oils such asfish, marine, sperm, cod-liver, haliver, squalene, squalane, and sharkliver oil, oleic oils, and polyoxyethylated castor oil); alkyl or arylhalides having 1-30 carbon atoms and optionally more than one halogensubstituent; methylene chloride; monoethanolamine; petroleum benzin;trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenicacid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoicacid); polyglycol ester of 12-hydroxystearic acid and polyethyleneglycol (Solutol® HS-15, from BASF, Ludwigshafen, Germany);polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitanmonooleate.

Other pharmaceutically acceptable solvents for use in the invention arewell known to those of ordinary skill in the art, and are identified inThe Chemotherapy Source Book (Williams & Wilkens Publishing), TheHandbook of Pharmaceutical Excipients, (American PharmaceuticalAssociation, Washington, D.C., and The Pharmaceutical Society of GreatBritain, London, England, 1968), Modern Pharmaceutics, (G. Banker etal., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y., 1995), ThePharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw HillPublishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.,)(Marcel Dekker, Inc., New York, N.Y., 1980), Remington's PharmaceuticalSciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, Pa. 1995),The United States Pharmacopeia 24, The National Formulary 19, (NationalPublishing, Philadelphia, Pa. 2000), A. J. Spiegel et al., and Use ofNonaqueous Solvents in Parenteral Products, JOURNAL OF PHARMACEUTICALSCIENCES, Vol. 52, No. 10, pp. 917-927 (1963).

Preferred solvents include those known to stabilize the antitumorcompounds, such as oils rich in triglycerides, for example, saffloweroil, soybean oil or mixtures thereof, and alkyleneoxy modified fattyacid esters such as polyoxyl 40 hydrogenated castor oil andpolyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor®RH 40 solution). Commercially available triglycerides includeIntralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm,Sweden), Nutralipid® emulsion (McGaw, Irvine, Calif.), Liposyn® II 20%emulsion (a 20% fat emulsion solution containing 100 mg safflower oil,100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion(a 2% fat emulsion solution containing 100 mg safflower oil, 100 mgsoybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), natural or syntheticglycerol derivatives containing the docosahexaenoyl group at levelsbetween 25% and 100% by weight based on the total fatty acid content(Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro®(from Daito Enterprises, Los Angeles, Calif.), Soyacal®, andTravemulsion®. Ethanol is a preferred solvent for use in dissolving theantitumor compound to form solutions, emulsions, and the like.

Additional minor components can be included in the compositions of theinvention for a variety of purposes well known in the pharmaceuticalindustry. These components will for the most part impart propertieswhich enhance retention of the antitumor compound at the site ofadministration, protect the stability of the composition, control thepH, facilitate processing of the antitumor compound into pharmaceuticalformulations, and the like. Preferably, each of these components isindividually present in less than about 15 weight % of the totalcomposition, more preferably less than about 5 weight %, and mostpreferably less than about 0.5 weight % of the total composition. Somecomponents, such as fillers or diluents, can constitute up to 90 wt. %of the total composition, as is well known in the formulation art. Suchadditives include cryoprotective agents for preventing reprecipitationof the taxane, surface active, wetting or emulsifying agents (e.g.,lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylenestearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbialpreservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol,sorbic acid, thimerosal and paraben), agents for adjusting pH orbuffering agents (e.g., acids, bases, sodium acetate, sorbitanmonolaurate), agents for adjusting osmolarity (e.g., glycerin),thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol,stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose,tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes,flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g.,bentonites), adhesives, bulking agents, flavorings, sweeteners,adsorbents, fillers (e.g., sugars such as lactose, sucrose, mannitol, orsorbitol, cellulose, or calcium phosphate), diluents (e.g., water,saline, electrolyte solutions), binders (e.g., starches such as maizestarch, wheat starch, rice starch, or potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers,acacia), disintegrating agents (e.g., starches such as maize starch,wheat starch, rice starch, potato starch, or carboxymethyl starch,cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereofsuch as sodium alginate, croscarmellose sodium or crospovidone),lubricants (e.g., silica, talc, stearic acid or salts thereof such asmagnesium stearate, or polyethylene glycol), coating agents (e.g.,concentrated sugar solutions including gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide),and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodiumsulfite, dextrose, phenols, and thiophenols).

In a preferred embodiment, a pharmaceutical composition of the inventioncomprises at least one nonaqueous, pharmaceutically acceptable solventand an antitumor compound having a solubility in ethanol of at leastabout 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While not beingbound to a particular theory, it is believed that the ethanol solubilityof the antitumor compound may be directly related to its efficacy. Theantitumor compound can also be capable of being crystallized from asolution. In other words, a crystalline antitumor compound, such ascompound 1393, can be dissolved in a solvent to form a solution and thenrecrystallized upon evaporation of the solvent without the formation ofany amorphous antitumor compound. It is also preferred that theantitumor compound have an ID50 value (i.e, the drug concentrationproducing 50% inhibition of colony formation) of at least 4, 5, 6, 7, 8,9, or 10 times less that of paclitaxel when measured according to theprotocol set forth in the working examples.

Dosage form administration by these routes may be continuous orintermittent, depending, for example, upon the patient's physiologicalcondition, whether the purpose of the administration is therapeutic orprophylactic, and other factors known to and assessable by a skilledpractitioner.

Dosage and regimens for the administration of the pharmaceuticalcompositions of the invention can be readily determined by those withordinary skill in treating cancer. It is understood that the dosage ofthe antitumor compounds will be dependent upon the age, sex, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired. For any mode ofadministration, the actual amount of antitumor compound delivered, aswell as the dosing schedule necessary to achieve the advantageouseffects described herein, will also depend, in part, on such factors asthe bioavailability of the antitumor compound, the disorder beingtreated, the desired therapeutic dose, and other factors that will beapparent to those of skill in the art. The dose administered to ananimal, particularly a human, in the context of the present inventionshould be sufficient to effect the desired therapeutic response in theanimal over a reasonable period of time. Preferably, an effective amountof the antitumor compound, whether administered orally or by anotherroute, is any amount which would result in a desired therapeuticresponse when administered by that route. Preferably, the compositionsfor oral administration are prepared in such a way that a single dose inone or more oral preparations contains at least 20 mg of the antitumorcompound per m²of patient body surface area, or at least 50, 100, 150,200, 300, 400, or 500 mg of the antitumor compound per m² of patientbody surface area, wherein the average body surface area for a human is1.8 m². Preferably, a single dose of a composition for oraladministration contains from about 20 to about 600 mg of the antitumorcompound per m² of patient body surface area, more preferably from about25 to about 400 mg/m², even more preferably, from about 40 to about 300mg/m², and even more preferably from about 50 to about 200 mg/m².Preferably, the compositions for parenteral administration are preparedin such a way that a single dose contains at least 20 mg of theantitumor compound per m²of patient body surface area, or at least 40,50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m²of patient body surface area. Preferably, a single dose in one or moreparenteral preparations contains from about 20 to about 500 mg of theantitumor compound per m² of patient body surface area, more preferablyfrom about 40 to about 400 mg/m², and even more preferably, from about60 to about 350 mg/m². However, the dosage may vary depending on thedosing schedule which can be adjusted as necessary to achieve thedesired therapeutic effect. It should be noted that the ranges ofeffective doses provided herein are not intended to limit the inventionand represent preferred dose ranges. The most preferred dosage will betailored to the individual subject, as is understood and determinable byone of ordinary skill in the art without undue experimentation.

The concentration of the antitumor compound in a liquid pharmaceuticalcomposition is preferably between about 0.01 mg and about 10 mg per mlof the composition, more preferably between about 0.1 mg and about 7 mgper ml, even more preferably between about 0.5 mg and about 5 mg per ml,and most preferably between about 1.5 mg and about 4 mg per ml.Relatively low concentrations are generally preferred because theantitumor compound is most soluble in the solution at lowconcentrations. The concentration of the antitumor compound in a solidpharmaceutical composition for oral administration is preferably betweenabout 5 weight % and about 50 weight %, based on the total weight of thecomposition, more preferably between about 8 weight % and about 40weight %, and most preferably between about 10 weight % and about 30weight %.

In one embodiment, solutions for oral administration are prepared bydissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis a solution, such as Cremophor® EL solution, is added to the solutionwhile stirring to form a pharmaceutically acceptable solution for oraladministration to a patient. If desired, such solutions can beformulated to contain a minimal amount of, or to be free of, ethanol,which is known in the art to cause adverse physiological effects whenadministered at certain concentrations in oral formulations.

In another embodiment, powders or tablets for oral administration areprepared by dissolving an antitumor compound in any pharmaceuticallyacceptable solvent capable of dissolving the compound (e.g., ethanol ormethylene chloride) to form a solution. The solvent can optionally becapable of evaporating when the solution is dried under vacuum. Anadditional carrier can be added to the solution prior to drying, such asCremophor® EL solution. The resulting solution is dried under vacuum toform a glass. The glass is then mixed with a binder to form a powder.The powder can be mixed with fillers or other conventional tablettingagents and processed to form a tablet for oral administration to apatient. The powder can also be added to any liquid carrier as describedabove to form a solution, emulsion, suspension or the like for oraladministration.

Emulsions for parenteral administration can be prepared by dissolving anantitumor compound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is an emulsion, suchas Liposyn® II or Liposyn® III emulsion, is added to the solution whilestirring to form a pharmaceutically acceptable emulsion for parenteraladministration to a patient. If desired, such emulsions can beformulated to contain a minimal amount of, or to be free of, ethanol orCremophor® solution, which are known in the art to cause adversephysiological effects when administered at certain concentrations inparenteral formulations.

Solutions for parenteral administration can be prepared by dissolving anantitumor compound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is a solution, suchas Cremophor® solution, is added to the solution while stirring to forma pharmaceutically acceptable solution for parenteral administration toa patient. If desired, such solutions can be formulated to contain aminimal amount of, or to be free of, ethanol or Cremophor® solution,which are known in the art to cause adverse physiological effects whenadministered at certain concentrations in parenteral formulations.

If desired, the emulsions or solutions described above for oral orparenteral administration can be packaged in IV bags, vials or otherconventional containers in concentrated form and diluted with anypharmaceutically acceptable liquid, such as saline, to form anacceptable taxane concentration prior to use as is known in the art.

Definitions

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with ahetero atom such as nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or a halogen atom. These substituents include halogen,heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol,ketals, acetals, esters and ethers.

The term “heteroatom” shall mean atoms other than carbon and hydrogen.

The “heterosubstituted methyl” moieties described herein are methylgroups in which the carbon atom is covalently bonded to at least oneheteroatom and optionally with hydrogen, the heteroatom being, forexample, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, orhalogen atom. The heteroatom may, in turn, be substituted with otheratoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy,hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol,ketals, acetals, esters or ether moiety.

The “heterosubstituted acetate” moieties described herein are acetategroups in which the carbon of the methyl group is covalently bonded toat least one heteroatom and optionally with hydrogen, the heteroatombeing, for example, a nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or halogen atom. The heteroatom may, in turn, be substitutedwith other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy,aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido,thiol, ketals, acetals, esters or ether moiety.

Unless otherwise indicated, the alkyl groups described herein arepreferably lower alkyl containing from one to eight carbon atoms in theprincipal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include methyl, ethyl, propyl, isopropyl,butyl, hexyl and the like.

Unless otherwise indicated, the alkenyl groups described herein arepreferably lower alkenyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include ethenyl, propenyl, isopropenyl,butenyl, isobutenyl, hexenyl, and the like.

Unless otherwise indicated, the alkynyl groups described herein arepreferably lower alkynyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain and include ethynyl, propynyl, butynyl, isobutynyl,hexynyl, and the like.

The terms “aryl” or “ar” as used herein alone or as part of anothergroup denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl or substituted naphthyl. Phenyl andsubstituted phenyl are the more preferred aryl.

The terms “halogen” or “halo” as used herein alone or as part of anothergroup refer to chlorine, bromine, fluorine, and iodine.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or nonaromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heterocyclo include heteroaromatics such as furyl,thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, orisoquinolinyl and the like. Exemplary substituents include one or moreof the following groups: hydrocarbyl, substituted hydrocarbyl, keto,hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy,aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals,esters and ethers.

The term “heteroaromatic” as used herein alone or as part of anothergroup denote optionally substituted aromatic groups having at least oneheteroatom in at least one ring, and preferably 5 or 6 atoms in eachring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may bebonded to the remainder of the molecule through a carbon or heteroatom.Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl,pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplarysubstituents include one or more of the following groups: hydrocarbyl,substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl,acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino,nitro, cyano, thiol, ketals, acetals, esters and ethers.

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxyl group from thegroup —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R isR¹, R¹O—, R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstitutedhydrocarbyl, or heterocyclo and R² is hydrogen, hydrocarbyl orsubstituted hydrocarbyl.

The term “acyloxy,” as used herein alone or as part of another group,denotes an acyl group as described above bonded through an oxygenlinkage (—O—), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.”

Unless otherwise indicated, the alkoxycarbonyloxy moieties describedherein comprise lower hydrocarbon or substituted hydrocarbon orsubstituted hydrocarbon moieties.

Unless otherwise indicated, the carbamoyloxy moieties described hereinare derivatives of carbamic acid in which one or both of the aminehydrogens is optionally replaced by a hydrocarbyl, substitutedhydrocarbyl or heterocyclo moiety.

The terms “hydroxyl protecting group” and “hydroxy protecting group” asused herein denote a group capable of protecting a free hydroxyl group(“protected hydroxyl”) which, subsequent to the reaction for whichprotection is employed, may be removed without disturbing the remainderof the molecule. A variety of protecting groups for the hydroxyl groupand the synthesis thereof may be found in “Protective Groups in OrganicSynthesis” by T. W. Greene, John Wiley and Sons, 1981, or Fieser &Fieser. Exemplary hydroxyl protecting groups include methoxymethyl,1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl,tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl,t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and2,2,2-trichloroethoxymethyl.

As used herein, “Ac” means acetyl; “Bz” means benzoyl; “Et” means ethyl;“Me” means methyl; “Ph” means phenyl; “iPr” means isopropyl; “tBu” and“t-Bu” means tert-butyl; “R” means lower alkyl unless otherwise defined;“py” means pyridine or pyridyl; “TES” means triethylsilyl; “TMS” meanstrimethylsilyl; “LAH” means lithium aluminum hydride; “10-DAB” means10-desacetylbaccatin III”; “amine protecting group” includes, but is notlimited to, carbamates, for example, 2,2,2-trichloroethylcarbamate ortertbutylcarbamate; “protected hydroxy” means —OP wherein P is a hydroxyprotecting group; “tBuOCO” means tert-butoxycarbonyl; “tAmOCO” meanstert-amyloxycarbonyl; “PhCO means phenylcarbonyl”; “2-FuCO” means2-furylcarbonyl; “2-ThCO” means 2-thienylcarbonyl; “2-PyCO” means2-pyridylcarbonyl; “3-PyCO” means 3-pyridylcarbonyl; “4-PyCO” means4-pyridylcarbonyl; “C₄H₇CO” means butenylcarbonyl; “EtOCO” meansethoxycarbonyl; “ibueCO” means isobutenylcarbonyl; “iBuCO” meansisobutylcarbonyl; “iBuOCO” means isobutoxycarbonyl; “iPrOCO” meansisopropyloxycarbonyl; “nPrOCO” means n-propyloxycarbonyl; “nPrCO” meansn-propylcarbonyl; “tC₃H₅CO” means trans-propenyl carbonyl ; “ibue” meansisobutenyl; “THF” means tetrahydrofuran; “DMAP” means 4-dimethylaminopyridine; and “LHMDS” means lithium hexamethyl disilazanide.

The following examples illustrate the invention.

EXAMPLE 1

N-Debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-10-methoxyacetyltaxol (6515)

To a solution ofN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-2′-(2-methoxy-2-propyl)-7-benzyloxycarbonyl-10-deacetyl-10-trimethylsilyltaxol (3.50 g) in 40 mL of 1:1 acetonitrile-pyridine at 0° C. (ice-waterbath) was added dropwise over 10 minutes, 10 mL of 48% aqueoushydrofluoric acid. The cooling bath was then removed and the reactionstirred at ambient temperature for 8 h, diluted with 200 mL of ethylacetate and washed with 25 mL of water, 2×20 mL of saturated aqueousNaHCO₃ and 25 mL of saturated aqueous NaCl. The organic layer was thendried over sodium sulfate and concentrated under reduced pressure togiveN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxycarbonyl-10-deacetyltaxol as a white solid which was dried under high vacuum (0.1 mmHg, 12h) and used directly in the next step.

To a solution ofN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxycarbonyl-10-deacetyltaxol (2.17 g, 2.293 mmol) in anhydrous methylene chloride (6 mL) wasadded with stirring triethylamine (1.60 mL, 11.46 mmol) followed by thedropwise addition of 0.46 mL of triethylsilyl chloride. TLC of themixture (silica gel, 2:3 ethyl acetate:hexane) after 2 h, showed theformation of only one product. Saturated aqueous NaHCO₃, 2 mL was addedto the reaction which was then diluted with 70 mL of ethyl acetate,washed with 10 mL of saturated aqueous NaHCO₃ and 15 mL of saturatedaqueous NaCl. The organic layer was dried over sodium sulfate andconcentrated under reduced pressure to give pureN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-2′-triethylsilyl-7-benzyloxycarbonyl-10-deacetyltaxol as a white solid (2.21 g, 91%)

To a solution ofN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-2′-triethylsilyl-7-benzyloxycarbonyl-10-deacetyltaxol (660 mg, 0.622 mmol) in 4 mL anhydrous pyridine at 0° C. was addedDMAP (20 mg, 0.16 mmol) under a nitrogen atmosphere. To this mixture wasadded drop wise methoxyacetyl chloride (220 mL, 2.489 mmol). TLC (silicagel, 2:3 ethyl acetate:hexane) after 2 h showed no starting material.The reaction was cooled to 0° C. (ice-water bath) and quenched by adding80 mL of water.

To the reaction at 0° C. (ice-water bath) was added 4 mL of acetonitrileand 2 mL of 48% aqueous hydrofluoric acid and the cooling bath wasremoved. The reaction was stirred at room temperature for 8.0 h, dilutedwith 60 mL of ethyl acetate and washed with 10 mL of saturated aqueousNaHCO₃ and 15 mL of saturated aqueous NaCl. The organic layer was driedover Na₂SO₄ and concentrated under reduce pressure to give 602 mg of ayellow solid which was purified by flash-chromatography (silica gel, 1:1ethyl acetate:hexane) to give 538 mg (85%) of pureN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxycarbonyl-10-deacetyl-10-methoxyacetyltaxol (TL-650): mp 145-146° C. ; Anal. Calcd. for C₅₃H₆₃NO₁₉:C, 62.53;H, 6.24. Found: C, 62.26; H, 6.20.

To a solution ofN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxycarbonyl-10-deacetyl-10-methoxyacetyltaxol (TL-650, 350 mg, 0.343 mmol) in 15 mL ethyl acetate was added 10%Pd-C (100 mg). The mixture was stirred under a H₂ atmosphere (usinglatex balloons)for 1 h, when TLC (silica gel, 1:1 ethyl acetate:hexane)showed no starting material. The reaction was then filtered throughcelite (3 g) and the celite pad washed with 25 mL of ethyl acetate. Thecombined organic extract was concentrated under reduced pressure to give315 mg of a white solid which was purified by flash-chromatography(silica gel, 55:45 ethyl acetate:hexane) to give 283 mg (93%) of pureN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-10-deacetyl-10-methoxyacetyltaxol: mp 164-166° C.; ¹H NMR (CDCl₃) 8.13 (m, 2H), 7.62 (m, 1H),7.46-7.51 (m, 2H), 7.41 (m, 1H), 6.41 (bs, 1H), 6.39 (dd, J=3.1, 1.5 Hz,1H), 6.25 (d, J=3.1 Hz, 1H), 6.22 (dd, J=8.8, 8.7 Hz, 1H), 5.67(1H),5.22-5.38 (m, 2H), 4.98(m, 1H), 4.76(m, 1H), 4.42(m, 2H), 4.36 (d, J=9.3Hz, 1H), 4.28 (m, 1H), 4.21 (d, J=9.3 Hz, 1H), 3.82 (m, 1H), 3.42 (s,3H), 3.41 (d, J=5.5 Hz, 1H), 2.55-2.60 (m, 1H), 2.41 (s, 3H), 2.20-2.38(m, 2H), 1.92 (s, 3H), 1.91-1.94 (m, 1H), 1.68 (bs, 3H), 1.62-1.68 (m,2H), 1.62 (S, 3H), 1.36 (s, 3H), 1.34 (s, 3H) 1.23 (s, 3H), 1.16 (s,3H), 0.80 (t, J=8.2 Hz, 3H); Anal. Calcd. for C₄₅H₅₇NO₁₇.½H₂O: C, 60.47;H, 6.49. Found: C, 60.64; H, 6.45.

EXAMPLE 2

The procedures described in Example 1 were repeated, but other suitablyprotected β-lactams were substituted for the β-lactam of Example 1 toprepare the series of compounds having structural formula (13) and thecombinations of substituents identified in the following table

(13)

Compound X₅ X₃ R₁₀ 6577 tAmOCO 2-furyl AcOAcO— 6515 tAmOCO 2-furylMeOAcO— 6066 tC₃H₅CO 2-furyl MeOAcO— 6111 tC₃H₅CO 2-furyl PhOAcO—

EXAMPLE 3

Following the processes described in Example 1 and elsewhere herein, thefollowing specific taxanes having structural formula 14 may be prepared,wherein R₁₀ is R_(10a)COO— and R_(10a) is heterosubstituted methyl. Inone embodiment, R_(10a) is chloromethyl, hydroxymethyl, methoxymethyl,ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, ormethylthiomethyl.

(14)

X₅ X₃ R₁₀ tBuOCO— 2-furyl R_(10a)COO— tBuOCO— 3-furyl R_(10a)COO—tBuOCO— 2-thienyl R_(10a)COO— tBuOCO— 3-thienyl R_(10a)COO— tBuOCO—2-pyridyl R_(10a)COO— tBuOCO— 3-pyridyl R_(10a)COO— tBuOCO— 4-pyridylR_(10a)COO— tBuOCO— isobutenyl R_(10a)COO— tBuOCO— isopropyl R_(10a)COO—tBuOCO— cyclopropyl R_(10a)COO— tBuOCO— cyclobutyl R_(10a)COO— tBuOCO—cyclopentyl R_(10a)COO— tBuOCO— phenyl R_(10a)COO— benzoyl 2-furylR_(10a)COO— benzoyl 3-furyl R_(10a)COO— benzoyl 2-thienyl R_(10a)COO—benzoyl 3-thienyl R_(10a)COO— benzoyl 2-pyridyl R_(10a)COO— benzoyl3-pyridyl R_(10a)COO— benzoyl 4-pyridyl R_(10a)COO— benzoyl isobutenylR_(10a)COO— benzoyl isopropyl R_(10a)COO— benzoyl cyclopropylR_(10a)COO— benzoyl cyclobutyl R_(10a)COO— benzoyl cyclopentylR_(10a)COO— benzoyl phenyl R_(10a)COO— 2-FuCO— 2-furyl R_(10a)COO—2-FuCO— 3-furyl R_(10a)COO— 2-FuCO— 2-thienyl R_(10a)COO— 2-FuCO—3-thienyl R_(10a)COO— 2-FuCO— 2-pyridyl R_(10a)COO— 2-FuCO— 3-pyridylR_(10a)COO— 2-FuCO— 4-pyridyl R_(10a)COO— 2-FuCO— isobutenyl R_(10a)COO—2-FuCO— isopropyl R_(10a)COO— 2-FuCO— cyclopropyl R_(10a)COO— 2-FuCO—cyclobutyl R_(10a)COO— 2-FuCO— cyclopentyl R_(10a)COO— 2-FuCO— phenylR_(10a)COO— 2-ThCO— 2-furyl R_(10a)COO— 2-ThCO— 3-furyl R_(10a)COO—2-ThCO— 2-thienyl R_(10a)COO— 2-ThCO— 3-thienyl R_(10a)COO— 2-ThCO—2-pyridyl R_(10a)COO— 2-ThCO— 3-pyridyl R_(10a)COO— 2-ThCO— 4-pyridylR_(10a)COO— 2-ThCO— isobutenyl R_(10a)COO— 2-ThCO— isopropyl R_(10a)COO—2-ThCO— cyclopropyl R_(10a)COO— 2-ThCO— cyclobutyl R_(10a)COO— 2-ThCO—cyclopentyl R_(10a)COO— 2-ThCO— phenyl R_(10a)COO— 2-PyCO— 2-furylR_(10a)COO— 2-PyCO— 3-furyl R_(10a)COO— 2-PyCO— 2-thienyl R_(10a)COO—2-PyCO— 3-thienyl R_(10a)COO— 2-PyCO— 2-pyridyl R_(10a)COO— 2-PyCO—3-pyridyl R_(10a)COO— 2-PyCO— 4-pyridyl R_(10a)COO— 2-PyCO— isobutenylR_(10a)COO— 2-PyCO— isopropyl R_(10a)COO— 2-PyCO— cyclopropylR_(10a)COO— 2-PyCO— cyclobutyl R_(10a)COO— 2-PyCO— cyclopentylR_(10a)COO— 2-PyCO— phenyl R_(10a)COO— 3-PyCO— 2-furyl R_(10a)COO—3-PyCO— 3-furyl R_(10a)COO— 3-PyCO— 2-thienyl R_(10a)COO— 3-PyCO—3-thienyl R_(10a)COO— 3-PyCO— 2-pyridyl R_(10a)COO— 3-PyCO— 3-pyridylR_(10a)COO— 3-PyCO— 4-pyridyl R_(10a)COO— 3-PyCO— isobutenyl R_(10a)COO—3-PyCO— isopropyl R_(10a)COO— 3-PyCO— cyclopropyl R_(10a)COO— 3-PyCO—cyclobutyl R_(10a)COO— 3-PyCO— cyclopentyl R_(10a)COO— 3-PyCO— phenylR_(10a)COO— 4-PyCO— 2-furyl R_(10a)COO— 4-PyCO— 3-furyl R_(10a)COO—4-PyCO— 2-thienyl R_(10a)COO— 4-PyCO— 3-thienyl R_(10a)COO— 4-PyCO—2-pyridyl R_(10a)COO— 4-PyCO— 3-pyridyl R_(10a)COO— 4-PyCO— 4-pyridylR_(10a)COO— 4-PyCO— isobutenyl R_(10a)COO— 4-PyCO— isopropyl R_(10a)COO—4-PyCO— cyclopropyl R_(10a)COO— 4-PyCO— cyclobutyl R_(10a)COO— 4-PyCO—cyclopentyl R_(10a)COO— 4-PyCO— phenyl R_(10a)COO— C₄H₇CO— 2-furylR_(10a)COO— C₄H₇CO— 3-furyl R_(10a)COO— C₄H₇CO— 2-thienyl R_(10a)COO—C₄H₇CO— 3-thienyl R_(10a)COO— C₄H₇CO— 2-pyridyl R_(10a)COO— C₄H₇CO—3-pyridyl R_(10a)COO— C₄H₇CO— 4-pyridyl R_(10a)COO— C₄H₇CO— isobutenylR_(10a)COO— C₄H₇CO— isopropyl R_(10a)COO— C₄H₇CO— cyclopropylR_(10a)COO— C₄H₇CO— cyclobutyl R_(10a)COO— C₄H₇CO— cyclopentylR_(10a)COO— C₄H₇CO— phenyl R_(10a)COO— EtOCO— 2-furyl R_(10a)COO— EtOCO—3-furyl R_(10a)COO— EtOCO— 2-thienyl R_(10a)COO— EtOCO— 3-thienylR_(10a)COO— EtOCO— 2-pyridyl R_(10a)COO— EtOCO— 3-pyridyl R_(10a)COO—EtOCO— 4-pyridyl R_(10aCOO—) EtOCO— isobutenyl R_(10a)COO— EtOCO—isopropyl R_(10a)COO— EtOCO— cyclopropyl R_(10a)COO— EtOCO— cyclobutylR_(10a)COO— EtOCO— cyclopentyl R_(10a)COO— EtOCO— phenyl R_(10a)COO—ibueCO- 2-furyl R_(10a)COO— ibueCO- 3-furyl R_(10a)COO— ibueCO-2-thienyl R_(10a)COO— ibueCO- 3-thienyl R_(10a)COO— ibueCO- 2-pyridylR_(10a)COO— ibueCO- 3-pyridyl R_(10a)COO— ibueCO- 4-pyridyl R_(10a)COO—ibueCO- isobutenyl R_(10a)COO— ibueCO- isopropyl R_(10a)COO— ibueCO-cyclopropyl R_(10a)COO— ibueCO- cyclobutyl R_(10a)COO— ibueCO-cyclopentyl R_(10a)COO— ibueCO- phenyl R_(10a)COO— iBuCO— 2-furylR_(10a)COO— iBuCO— 3-furyl R_(10a)COO— iBuCO— 2-thienyl R_(10a)COO—iBuCO— 3-thienyl R_(10a)COO— iBuCO— 2-pyridyl R_(10a)COO— iBuCO—3-pyridyl R_(10a)COO— iBuCO— 4-pyridyl R_(10a)COO— iBuCO— isobutenylR_(10a)COO— iBuCO— isopropyl R_(10a)COO— iBuCO— cyclopropyl R_(10a)COO—iBuCO— cyclobutyl R_(10a)COO— iBuCO— cyclopentyl R_(10a)COO— iBuCO—phenyl R_(10a)COO— iBuOCO— 2-furyl R_(10a)COO— iBuOCO— 3-furylR_(10a)COO— iBuOCO— 2-thienyl R_(10a)COO— iBuOCO— 3-thienyl R_(10a)COO—iBuOCO— 2-pyridyl R_(10a)COO— iBuOCO— 3-pyridyl R_(10a)COO— iBuOCO—4-pyridyl R_(10a)COO— iBuOCO— isobutenyl R_(10a)COO— iBuOCO— isopropylR_(10a)COO— iBuOCO— cyclopropyl R_(10a)COO— iBuOCO— cyclobutylR_(10a)COO— iBuOCO— cyclopentyl R_(10a)COO— iBuOCO— phenyl R_(10a)COO—iPrOCO— 2-furyl R_(10a)COO— iPrOCO— 3-furyl R_(10a)COO— iPrOCO—2-thienyl R_(10a)COO— iPrOCO— 3-thienyl R_(10a)COO— iPrOCO— 2-pyridylR_(10a)COO— iPrOCO— 3-pyridyl R_(10a)COO— iPrOCO— 4-pyridyl R_(10a)COO—iPrOCO— isobutenyl R_(10a)COO— iPrOCO— isopropyl R_(10a)COO— iPrOCO—cyctopropyl R_(10a)COO— iPrOCO— cyclobutyl R_(10a)COO— iPrOCO—cyclopentyl R_(10a)COO— iPrOCO— phenyl R_(10a)COO— nPrOCO— 2-furylR_(10a)COO— nPrOCO— 3-furyl R_(10a)COO— nPrOCO— 2-thienyl R_(10a)COO—nPrOCO— 3-thienyl R_(10a)COO— nPrOCO— 2-pyridyl R_(10a)COO— nPrOCO—3-pyridyl R_(10a)COO— nPrOCO— 4-pyridyl R_(10a)COO— nPrOCO— isobutenylR_(10a)COO— nPrOCO— isopropyl R_(10a)COO— nPrOCO— cyclopropylR_(10a)COO— nPrOCO— cyclobutyl R_(10a)COO— nPrOCO— cyclopentylR_(10a)COO— nPrOCO— phenyl R_(10a)COO— nPrCO— 2-furyl R_(10a)COO— nPrCO—3-furyl R_(10a)COO— nPrCO— 2-thienyl R_(10a)COO— nPrCO— 3-thienylR_(10a)COO— nPrCO— 2-pyridyl R_(10a)COO— nPrCO— 3-pyridyl R_(10a)COO—nPrCO— 4-pyridyl R_(10a)COO— nPrCO— isobutenyl R_(10a)COO— nPrCO—isopropyl R_(10a)COO— nPrCO— cyclopropyl R_(10a)COO— nPrCO— cyclobutylR_(10a)COO— nPrCO— cyclopentyl R_(10a)COO— nPrCO— phenyl R_(10a)COO—

EXAMPLE 4

Following the processes described in Example 1 and elsewhere herein, thefollowing specific taxanes having structural formula 15 may be prepared,wherein R₇ is hydroxy and R₁₀ in each of the series (that is, each ofseries “A” through “K”) is as previously defined, including wherein R₁₀is R_(10a)COO— wherein R_(10a) is a heterosubstituted methyl moietylacking a carbon atom which is in the beta position relative to thecarbon atom of which R_(10a) is a substituent. The heterosubstitutedmethyl is covalently bonded to at least one heteroatom and optionallywith hydrogen, the heteroatom being, for example, a nitrogen, oxygen,silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatommay, in turn, be substituted with other atoms to form a heterocyclo,alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy,acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ethermoiety. Exemplary R₁₀ substituents include R_(10a)COO— wherein R_(10a)is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl,phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl.

In the “A” series of compounds, X₁₀ is as otherwise as defined herein.Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl,or pyridyl, X₁₀ is substituted or unsubstitued furyl, thienyl, pyridyl,phenyl, or lower alkyl (e.g., tert-butyl), and R₇ and R₁₀ each have thebeta stereochemical configuration.

In the “B” series of compounds, X₁₀ and R_(2a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

In the “C” series of compounds, X₁₀ and R_(9a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(9a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “D” and “E” series of compounds, X₁₀ is as otherwise as definedherein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), and R₇, R₉ (series D only) and R₁₀ each have the betastereochemical configuration.

In the “F” series of compounds, X₁₀, R_(2a) and R_(9a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “G” series of compounds, X₁₀ and R_(2a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “H” series of compounds, X₁₀ is as otherwise as defined herein.Preferably, heterocyclo is preferably substituted or unsubstitued furyl,thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstituedfuryl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl),R_(2a) is preferably substituted or unsubstitued furyl, thienyl,pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have the betastereochemical configuration.

In the “I” series of compounds, X₁₀ and R_(2a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

In the “J” series of compounds, X₁₀ and R_(2a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “K” series of compounds, X₁₀, R_(2a) and R_(9a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

Any substituents of each X₃, X₅, R₂, R₇, and R₉ may be hydrocarbyl orany of the heteroatom containing substituents selected from the groupconsisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy,protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal,acetal, ester and ether moieties, but not phosphorous containingmoieties.

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Series X₅ X₃ R₁₀ R₂ R₉ R₁₄ A1 —COOX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OH A2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— O H A3 —CONHX₁₀ heterocycloR_(10a)COO— C₆H₅COO— O H A4 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— O Hsubstituted C₂ to C₈ alkyl A5 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— O Hsubstituted C₂ to C₈ alkyl A6 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH substituted C₂ to C₈ alkyl A7 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO—O H substituted C₂ to C₈ alkenyl A8 —COX₁₀ optionally R_(10a)COO—C₆H₅COO— O H substituted C₂ to C₈ alkenyl A9 —CONHX₁₀ optionallyR_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkenyl A10 —COOX₁₀optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkynyl A11—COX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkynylA12 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈alkynyl B1 —COOX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— O H B2 —COX₁₀heterocyclo R_(10a)COO— R_(2a)COO— O H B3 —CONHX₁₀ heterocycloR_(10a)COO— R_(2a)COO— O H B4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO—O H substituted C₂ to C₈ alkyl B5 —COX₁₀ optionally R_(10a)COO—R_(2a)COO— O H substituted C₂ to C₈ alkyl B6 —CONHX₁₀ optionallyR_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkyl B7 —COOX₁₀optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkenyl B8—COX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈alkenyl B9 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂to C₈ alkenyl B10 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O Hsubstituted C₂ to C₈ alkynyl B11 —COX₁₀ optionally R_(10a)COO—R_(2a)COO— O H substituted C₂ to C₈ alkynyl B12 —CONHX₁₀ optionallyR_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkynyl C1 —COOX₁₀heterocyclo R_(10a)COO— C₆H₅COO— R_(9a)COO— H C2 —COX₁₀ heterocycloR_(10a)COO— C₆H₅COO— R_(9a)COO— H C3 —CONHX₁₀ heterocyclo R_(10a)COO—C₆H₅COO— R_(9a)COO— H C4 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO—R_(9a)COO— H substituted C₂ to C₈ alkyl C5 —COX₁₀ optionally R_(10a)COO—C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkyl C6 —CONHX₁₀ optionallyR_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkyl C7 —COOX₁₀optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈alkenyl C8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl C9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO—R_(9a)COO— H substituted C₂ to C₈ alkenyl C10 —COOX₁₀ optionallyR_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl C11—COX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈alkynyl C12 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO R_(9a)COO— Hsubstituted C₂ to C₈ alkynyl D1 —COOX₁₀ heterocyclo R_(10a)COO— C₆H₅COO—OH H D2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OH H D3 —CONHX₁₀heterocyclo R_(10a)COO— C₆H₅COO— OH H D4 —COOX₁₀ optionally R_(10a)COO—C₆H₅COO— OH H substituted C₂ to C₈ alkyl D5 —COX₁₀ optionallyR_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D6 —CONHX₁₀optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D7—COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈alkenyl D8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ toC₈ alkenyl D9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substitutedC₂ to C₈ alkenyl D10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH Hsubstituted C₂ to C₈ alkynyl D11 —COX₁₀ optionally R_(10a)COO— C₆H₅COO—OH H substituted C₂ to C₈ alkynyl D12 —CONHX₁₀ optionally R_(10a)COO—C₆H₅COO— OH H substituted C₂ to C₈ alkynyl E1 —COOX₁₀ heterocycloR_(10a)COO— C₆H₅COO— O OH E2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OOH E3 —CONHX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— O OH E4 —COOX₁₀optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkyl E5—COX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkylE6 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈alkyl E7 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ toC₈ alkenyl E8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂to C₈ alkenyl E9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O OHsubstituted C₂ to C₈ alkenyl E10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO—O OH substituted C₂ to C₈ alkynyl E11 —COX₁₀ optionally R_(10a)COO—C₆H₅COO— O OH substituted C₂ to C₈ alkynyl E12 —CONHX₁₀ optionallyR_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkynyl F1 —COOX₁₀heterocyclo R₁₀—COO— R_(2a)COO— R_(9a)COO— H F2 —COX₁₀ heterocycloR_(10a)COO— R_(2a)COO— R_(9a)COO— H F3 —CONHX₁₀ heterocyclo R_(10a)COO—R_(2a)COO— R_(9a)COO— H F4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO—R_(9a)COO— H substituted C₂ to C₈ alkyl F5 —COX₁₀ optionally R_(10a)COO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkyl F6 —CONHX₁₀optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈alkyl F7 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl F8 —COX₁₀ optionally R_(10a)COO— R_(2a)COO—R_(9a)COO— H substituted C₂ to C₈ alkenyl F9 —CONHX₁₀ optionallyR_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl F10—COOX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ toC₈ alkynyl F11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkynyl F12 —CONHX₁₀ optionally R_(10a)COO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl G1 —OOOX₁₀heterocyclo R_(10a)COO— R_(2a)COO— OH H G2 —COX₁₀ heterocycloR_(10a)COO— R_(2a)COO— OH H G3 —CONHX₁₀ heterocyclo R_(10a)COO—R_(2a)COO— OH H G4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH Hsubstituted C₂ to C₈ alkyl G5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO—OH H substituted C₂ to C₈ alkyl G6 —CONHX₁₀ optionally R_(10a)COO—R_(2a)COO— OH H substituted C₂ to C₈ alkyl G7 —COOX₁₀ optionallyR_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G8 —COX₁₀optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G9—CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈alkenyl G10 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substitutedC₂ to C₈ alkynyl G11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH Hsubstituted C₂ to C₈ alkynyl G12 —CONHX₁₀ optionally R_(10a)COO—R_(2a)COO— OH H substituted C₂ to C₈ alkynyl H1 —COOX₁₀ heterocycloR_(10a)COO— C₆H₅COO— OH OH H2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OHOH H3 —CONHX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OH OH H4 —COOX₁₀optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkyl H5—COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkylH6 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈alkyl H7 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ toC₈ alkenyl H8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substitutedC₂ to C₈ alkenyl H9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OHsubstituted C₂ to C₈ alkenyl H10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO—OH OH substituted C₂ to C₈ alkynyl H11 —COX₁₀ optionally R_(10a)COO—C₆H₅COO— OH OH substituted C₂ to C₈ alkynyl H12 —CONHX₁₀ optionallyR_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkynyl I1 —COOX₁₀heterocyclo R_(10a)COO— R_(2a)COO— O OH I2 —COX₁₀ heterocycloR_(10a)COO— R_(2a)COO— O OH I3 —CONHX₁₀ heterocyclo R_(10a)COO—R_(2a)COO— O OH I4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O OHsubstituted C₂ to C₈ alkyl I5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OOH substituted C₂ to C₈ alkyl I6 —CONHX₁₀ optionally R_(10a)COO—R_(2a)COO— O OH substituted C₂ to C₈ alkyl I7 —COOX₁₀ optionallyR_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I8 —COX₁₀optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I9—CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈alkenyl I10 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substitutedC₂ to C₈ alkynyl I11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— O OHsubstituted C₂ to C₈ alkynyl I12 —CONHX₁₀ optionally R_(10a)COO—R_(2a)COO— O OH substituted C₂ to C₈ alkynyl J1 —COOX₁₀ heterocycloR_(10a)COO— R_(2a)COO— OH OH J2 —COX₁₀ heterocyclo R_(10a)COO—R_(2a)COO— OH OH J3 —CONHX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— OH OH J4—COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈alkyl J5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂to C₈ alkyl J6 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OHsubstituted C₂ to C₈ alkyl J7 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO—OH OH substituted C₂ to C₈ alkenyl J8 —COX₁₀ optionally R_(10a)COO—R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J9 —CONHX₁₀ optionallyR_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J10 —COOX₁₀optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkynyl J11—COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈alkynyl J12 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substitutedC₂ to C₈ alkynyl K1 —COOX₁₀ heterocyclo R_(10a)COO— R_(2a)COO—R_(9a)COO— OH K2 —COX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— R_(9a)COO— OHK3 —CONHX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— R_(9a)COO— OH K4 —COOX₁₀optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈alkyl K5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkyl K6 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO—R_(9a)COO— OH substituted C₂ to C₈ alkyl K7 —COOX₁₀ optionallyR_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkenyl K8—COX₁₀ optionally R_(10a)COO— R2_(a)COO— R_(9a)COO— OH substituted C₂ toC₈ alkenyl K9 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkenyl K10 —COOX₁₀ optionally R_(10a)COO—R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkynyl K11 —COX₁₀optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈alkynyl K12 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkynyl

EXAMPLE 5 In Vitro Cytotoxicity Measured by the Cell Colony FormationAssay

Four hundred cells (HCT116) were plated in 60 mm Petri dishes containing2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovineserum and 100 units/mL penicillin and 100 g/mL streptomycin). The cellswere incubated in a CO₂ incubator at 37° C. for 5 h for attachment tothe bottom of Petri dishes. The compounds identified in Example 2 weremade up fresh in medium at ten times the final concentration, and then0.3 mL of this stock solution was added to the 2.7 mL of medium in thedish. The cells were then incubated with drugs for 72 h at 37° C. At theend of incubation the drug-containing media were decanted, the disheswere rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL offresh medium was added, and the dishes were returned to the incubatorfor colony formation. The cell colonies were counted using a colonycounter after incubation for 7 days. Cell survival was calculated andthe values of ID50 (the drug concentration producing 50% inhibition ofcolony formation) were determined for each tested compound.

IN VITRO Compound ID 50 (nm) HCT116 taxol 2.1 docetaxel 0.6 6577 <1 6515<1 6066 <1 6111 <1

1. A taxane having the formula:

wherein R₂ is acyloxy; R₇ is hydroxy; R₉ is keto, hydroxy, or acyloxy;R₁₀ is acyloxyacetyloxy; R₁₄ is hydrido or hydroxy; X₃ is substituted orunsubstituted alkyl, alkenyl, or alkynyl or heterocyclo; X₅ is —COX₁₀,—COOX₁₀, or —CONHX₁₀; X₁₀ is hydrocarbyl, substituted hydrocarbyl, orheterocyclo; and Ac is acetyl.
 2. The taxane of claim 1 wherein X₃ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 3. The taxane of claim 1wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 4. The taxane of claim 1 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 5. The taxane of claim 1wherein R₁₄ is hydrido.
 6. The taxane of claim 5 wherein X₃ is 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 7. The taxane of claim 5 whereinX₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ issubstituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 8. The taxane of claim 5 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 9. The taxane of claim 1wherein R₂ is benzoyloxy.
 10. The taxane of claim 9 wherein X₃ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 11. The taxane of claim 9wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ issubstituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 12. The taxane of claim 9 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 13. The taxane of claim 1wherein R₁₄ is hydrido and R₉ is keto.
 14. The taxane of claim 13wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl. 15.The taxane of claim 13 wherein X₅ is —COX₁₀ and X₁₀ is substituted orunsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 16. The taxane of claim 13 wherein X₅ is—COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 17. Thetaxane of claim 1 wherein R₂ is benzoyloxy and R₉ is keto.
 18. Thetaxane of claim 17 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 19. The taxane of claim 17 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 20. Thetaxane of claim 17 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 21. The taxane of claim 1 wherein R₁₄ ishydrido and R₂ is benzoyloxy.
 22. The taxane of claim 21 wherein X₃ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 23. The taxane of claim 21wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ issubstituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 24. The taxane of claim 21 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 25. The taxane of claim 1wherein R₁₄ is hydrido, R₉ is keto, and R₂ is benzoyloxy.
 26. The taxaneof claim 25 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 27. The taxane of claim 25 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C_(1 -C) ₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl or X₅is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 28. Thetaxane of claim 25 wherein X₅is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 29. The taxane of claim 25 wherein X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 30. The taxane of claim 29 wherein X₃ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,cycloalkyl or alkenyl.
 31. The taxane of claim 29 wherein X₃ is furyl orthienyl.
 32. The taxane of claim 29 wherein X₃ is cycloalkyl.
 33. Ataxane having the formula

R₇ is hydroxy; R₁₀ is R_(10a)COO—; R_(10a) is a heterosubstituted methylgroup wherein the heteroatom may be substituted to form a heterocyclo,alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy,acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester or ether; X₃is substituted or unsubstituted alkyl, alkenyl, or alkynyl orheterocyclo; X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; and X₁₀ is hydrocarbyl,substituted hydrocarbyl, or heterocyclo.
 34. The taxane of claim 33wherein X₃ is furyl, thienyl, pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, orC₂-C₈ alkynyl.
 35. The taxane of claim 33 wherein R₁₀ is R_(10a)COO— andR_(10a) is a heterosubstituted methyl group wherein the heteroatom maybe substituted to form a alkoxy, alkenoxy, aryloxy, hydroxy, acyloxy,ester or ether.
 36. The taxane of claim 33 wherein R₁₀ is R_(10a)COO—and R_(10a) is a heterosubstituted methyl group wherein the heteroatommay be substituted to form an alkoxy or aryloxy.
 37. The taxane of claim34 wherein X₃ is furyl or thienyl.
 38. A pharmaceutical compositioncomprising the taxane of claim 1 and at least one pharmaceuticallyacceptable carrier.
 39. The pharmaceutical composition of claim 38wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl. 40.The pharmaceutical composition of claim 39 wherein X₅ is —COX₁₀ and X₁₀is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 41. Thepharmaceutical composition of claim 39 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 42. The pharmaceuticalcomposition of claim 39 wherein X₃ is substituted or unsubstituted furylor thienyl, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ andX₁₀ is t-butyl.
 43. The pharmaceutical composition of claim 39 whereinX₃ is furyl or thienyl, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is—COOX₁₀ wherein X₁₀ is t-butyl.
 44. The pharmaceutical composition ofclaim 39 wherein X₃ is alkyl or isobutenyl, and X₅ is —COX₁₀ wherein X₁₀is phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 45. Thepharmaceutical composition of claim 39 wherein X₃ is furyl or thienyl,X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 46. The pharmaceutical composition ofclaim 39 wherein X₃ is isobutenyl or alkyl, X₅ is —COOX₁₀ and X₁₀ ist-butyl.
 47. A pharmaceutical composition comprising the taxane of claim34 and at least one pharmaceutically acceptable carrier.
 48. Apharmaceutical composition comprising the taxane of claim 37 and atleast one pharmaceutically acceptable carrier.
 49. A composition fororal administration comprising the taxane of claim 1 and at least onepharmaceutically acceptable carrier.
 50. The pharmaceutical compositionof claim 49 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈alkynyl.
 51. The pharmaceutical composition of claim 50 wherein X₅ is—COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl,C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substitutedor unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 52. Thepharmaceutical composition of claim 50 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 53. The pharmaceuticalcomposition of claim 50 wherein X₃ is substituted or unsubstituted furylor thienyl, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ andX₁₀ is t-butyl.
 54. A composition for oral administration comprising thetaxane of claim 34 and at least one pharmaceutically acceptable carrier.55. A composition for oral administration comprising the taxane of claim37 and at least one pharmaceutically acceptable carrier.
 56. A method ofinhibiting tumor growth in a mammal, said method comprising orallyadministering a therapeutically effective amount of a pharmaceuticalcomposition comprising the taxane of claim 1 and at least onepharmaceutically acceptable carrier.
 57. The method of claim 56 whereinX₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl.
 58. The methodof claim 57 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstitutedphenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is—COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 59. The method of claim 57 wherein X₅ is—COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 60. Themethod of claim 57 wherein X₃ is substituted or unsubstituted furyl orthienyl, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ andX₁₀ is t-butyl.
 61. A method of inhibiting tumor growth in a mammal,said method comprising orally administering a therapeutically effectiveamount of a pharmaceutical composition comprising the taxane of claim 34and at least one pharmaceutically acceptable carrier.
 62. A method ofinhibiting tumor growth in a mammal, said method comprising orallyadministering a therapeutically effective amount of a pharmaceuticalcomposition comprising the taxane of claim 37 and at least onepharmaceutically acceptable carrier.
 63. A taxane having the formula

wherein R₁₀ is acetyloxyacetyloxy or methoxyacetyloxy; X₃ is 2-furyl; X₅is —COOX₁₀ and X₁₀ is t-amyl; and Ac is acetyl.
 64. A taxane having theformula

wherein R₁₀ is methoxyacetyloxy or phenoxyacetyloxy; X₃ is 2-furyl; X₅is —COX₁₀ and X₁₀ is trans-propenyl; and Ac is acetyl.
 65. The taxane ofclaim 33 wherein X₃ is furyl or thienyl, X₅ is —COX₁₀ or —COOX₁₀, andX₁₀ is C₁-C₈ alkyl.
 66. The taxane of claim 33 wherein X₃ is furyl orthienyl, X₅ is —COX₁₀ or —COOX₁₀, and X₁₀ is C₂-C₈ alkenyl.
 67. Thetaxane of claim 33 wherein X₃ is furyl or thienyl, X₅ is —COX₁₀ and X₁₀is substituted or unsubstituted phenyl.
 68. The taxane of any of claims65 to 67 wherein R_(10a) is chloromethyl, hydroxymethyl, methoxymethyl,ethoxymethyl, acetyloxymethyl, or methylthiomethyl.
 69. The taxane ofany of claims 65 to 67 wherein R_(10a) is chloromethyl, hydroxymethyl,methoxymethyl, ethoxymethyl, acetyloxymethyl, methylthiomethyl, orphenylmethyl.
 70. The taxane of claim 1 wherein X₃ is heterocyclic, R₁₀is acetyloxyacetyloxy, X₅ is —COOX₁₀, and X₁₀ is C₁₋₈ alkyl.
 71. Thetaxane of claim 70 wherein X₃ is furyl, thienyl or pyridyl.
 72. Thetaxane of claim 71 wherein X₁₀ is methyl, ethyl, or straight, branchedor cyclic propyl, butyl, pentyl or hexyl.